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Metabolismo Biodispinibilidad
Excrecion. Sustancias Excipientes
Membranas biologicas o
compratimentos.
Receptores Farmacologicos
Farmacos pueden modificar respuestas celulares intrinsecas. No generar nuevas funciones
celulares.
Implica la existencia de components celulares que respondan a los farmacos, por union
reversible ( en algunos casos irreversibles).
Sitios especificos e inespecificos de union.
Las molculas con que los frmacos son capaces de interactuar selectivamente,
generndose como consecuencia de ello una modificacin constante y especfica en la
funcin celular, se denominan receptores farmacolgicos.
La afinidad de un frmaco por su receptor tiene que ser alta, con valores acordes con
Si a la concentracin de frmaco
fijado [AR] se la denomina B, a la
concentracin total de receptores
[AR] + [R] se la designa Bmx y a
la concentracin de A libre (no
unido a receptores) se la denomina
F, de acuerdo con la ecuacin [3]:
Representacion de Scatchard
Las causas ms frecuentes de este fenmeno son: a) la existencia de ms de un sitio de fijacin en
la poblacin marcada, con valores de afinidad diferentes, y b) interacciones de tipo cooperativo: la
fijacin de cada molcula del radioligando afecta la fijacin de las sucesivas molculas, bien de
forma favorecedora (cooperatividad positiva, curva hacia arriba) o perturbadora (cooperatividad
negativa, curva hacia abajo).
nH es el coeficiente de
Hill
Valores de nH
inferiores a la unidad
indican la existencia
de ms de un sitio de
unin o bien la de
cooperatividad
negativa.
Curvas de competicion
Perfiles de afinidad
Agonista .
Antagonista.
Fenomenos de adaptacion
e = Rt
una constante propia del frmaco, que indica
La posicin lateral de la curva a lo
largo del eje de abscisas indica la
potencia y se relaciona con la
afinidad del frmaco por su receptor.
A mayor potencia, menor cantidad
de frmaco ser necesaria para
conseguir un efecto determinado.
En el caso terico en que f es lineal,
la concentracin de frmaco
necesaria para conseguir la mitad
del efecto mximo expresa la KD y,
por lo tanto, la afinidad. Dicha
concentracin se denomina dosis
eficaz 50 o DE50.
Receptores de reserva
Evidencia demuestra que no es
necesario ocupar todos los
receptores para conseguir el
maximo efecto biologico.
Esta magnitud es variable
dependiendo de la eficacia de
un farmaco.
A medida que la funcin f se
aparta de la linealidad y se
utilizan frmacos agonistas
capaces de producir respuestas
con bajos niveles de ocupacin,
los valores de DE50 y KD se
separan, y la estimacin
funcional de la afinidad a partir
de la DE50 de la curva dosis-
efecto se vuelve inexacta.
Agonistas y antagonistas
Antagonistas
Antagonismo Quimico
Farmacocinetica
Pharmacokinetics is the study of the time
course (i.e., kinetics) of absorption,
distribution, metabolism, and excretion
(ADME) of drugs and their metabolites in the
body.
population pharmacokinetics
Paracelso and Dosis concept
Amount of xenobiotic at a site of administration, which will be subjected to the
physiological processes of ADME.
Alle Ding sind Gift und nichts ohn Gift; allein die Dosis macht, das ein Ding kein Gift ist. [All
substances are poisons; there is none which is not a poison. The right dose differentiates a poison
from a remedy.]
Diffusion trough compartments
[A] and [B] Figures show the concentration profile in a lipid membrane separating two aqueous
compartments. A lipid-soluble drug [A] is subject to a much larger transmembrane concentration
gradient (Cm) than a lipid-insoluble drug [B]. It therefore diffuses more rapidly, even though the
pH and ionization
DRUG INTERACTIONS CAUSED BY ALTERED DISTRIBUTION: One drug may alter the distribution
of another, by competing for a common binding site on plasma albumin or tissue protein, but such
interactions are seldom clinically important unless accompanied by a separate effect on drug
elimination.
Toxicity from the transient increase in concentration of free drug before the new steady state is
reached.
If dose is being adjusted according to measurements of total plasma concentration, it must be
appreciated that the target therapeutic concentration range will be altered by co-administration of a
displacing drug.
When the displacing drug additionally reduces elimination of the first, so that the free concentration
is increased not only acutely but also chronically at the new steady state, severe toxicity may ensue.
Drug metabolism and
elimination
Overview:
phases 1 and 2 of
drug metabolism
(cytochrome P450 )
monooxygenase
system .
biliary excretion
and enterohepatic
recirculation of
drugs.
drug interactions.
A Drug could be eliminated by 2process metabolism y excretion.
Metabolism involve catabolism and/or anabolism od a drug, and
excretion involves elimination of the drug from the organism by one
or several of the following routes:
the kidneys
the hepatobiliary system
the lungs (important for volatile/gaseous anaesthetics).
Milk (excretion into milk can sometimes be important because of
effects on the baby ).
Examples where this is important include morphine CLren varies greatly for different drugs, from
(Ch. 42) and ethinylestradiol (Ch. 35). Several less than 1 ml/min to the theoretical maximum
drugs are excreted to an appreciable extent in bile. set by the renal plasma flow, which is
Vecuronium (a non-depolarising muscle relaxant; approximately 700 ml/min, measured by p-
Ch. 13) is an example of a drug that is excreted aminohippuric acid (PAH) clearance (renal
mainly unchanged in bile. Rifampicin (Ch. 51) is extraction of PAH approaches 100%).
absorbed from the gut and slowly deacetylated,
retaining its biological activity.
Three fundamental processes account for renal drug excretion:
1. glomerular filtration
2. active tubular secretion
3. passive reabsorption (diffusion from the concentrated tubular
fluid back across tubular epithelium).
GLOMERULAR FILTRATION
Glomerular capillaries allow drug molecules of molecular weight
below about 20 kDa to pass into the glomerular filtrate.
TUBULAR SECRETION
Drug molecules are transferred to the tubular lumen by two
independent and relatively non-selective carrier systems. One of
these, the OAT, transports acidic drugs in their negatively charged
anionic form (as well as various endogenous acids, such as uric
acid), while an OCT handles organic bases in their protonated
cationic form.
The OAT carrier can transport drug molecules against an
electrochemical gradient, and can therefore reduce the plasma
concentration nearly to zero, whereas OCT facilitates transport
down an electrochemical gradient. Unlike glomerular filtration,
carrier-mediated transport can achieve maximal drug clearance
even when most of the drug is bound to plasma protein.
probenecid was developed originally to prolong the action of
penicillin by retarding its tubular secretion.
These exemplify a relatively small but
important group of drugs (Table 9.8)
that are not inactivated by
metabolism, the rate of renal
elimination being the main factor that
determines their duration of action.
These drugs have to be used with
special care in individuals whose renal
function may be impaired, including
the elderly and patients with renal
disease or any severe acute illness.
DRUG INTERACTIONS DUE TO ALTERED DRUG EXCRETION
Most current anticancer drugs, particularly cytotoxic agents, affect only one characteristic
aspect of cancer cell biology cell division but have no specific inhibitory effect on
invasiveness, the loss of differentiation or the tendency to metastasis.
Furthermore, because their main target is cell division, they will affect all rapidly dividing
normal tissues, and therefore are likely to produce, to a greater or lesser extent, the
following general toxic effects:
bone marrow toxicity (myelosuppression) with decreased leukocyte production and thus
decreased resistance to infection
impaired wound healing
loss of hair (alopecia)
damage to gastrointestinal epithelium (including oral mucous membranes)
depression of growth in children
sterility
teratogenicity
carcinogenicity because many cytotoxic drugs are mutagens.
Rapid cell destruction also entails extensive purine catabolism, and urates may
precipitate in the renal tubules and cause kidney damage.
Cytotoxic drugs. These include:
alkylating agents and related compounds, which act by forming covalent bonds with
DNA and thus impeding replication
antimetabolites, which block or subvert one or more of the metabolic pathways
involved in DNA synthesis
cytotoxic antibiotics, i.e. substances of microbial origin that prevent mammalian cell
division
plant derivatives (e.g. vinca alkaloids, taxanes, camptothecins): most of these
specifically affect microtubule function and hence the formation of the mitotic spindle.
Hormones, of which the most important are steroids (e.g. glucocorticoids, Ch. 33) as
well as drugs that suppress oestrogen synthesis (e.g. aromatase inhibitors) or the
secretion of male sex hormones (e.g. gonadorelin analogues, Ch. 35) or antagonise
hormone action (e.g. oestrogen and androgen antagonists, Ch. 35).
Protein kinase inhibitors: these drugs inhibit the protein kinases (usually tyrosine
kinases but sometimes others) involved in growth factor receptor signal transduction.
They are increasingly used in a range of specific malignancies (see Krause & van
Etten, 2005).
Monoclonal antibodies: of growing importance in particular types of cancer.
Miscellaneous agents that do not easily fit into the above categories.
ALKYLATING AGENTS AND RELATED COMPOUNDS
Alkylating agents and related compounds contain
chemical groups that can form covalent bonds with
particular nucleophilic substances in the cell (such as
DNA).
It has low lipid solubility and thus does not readily cross the blood
brain barrier.
Methotrexate is also used as an immunosuppressant drug to treat
rheumatoid arthritis, psoriasis and other autoimmune conditions.
Unwanted effects include depression of the bone marrow and
damage to the epithelium of the gastrointestinal tract. Pneumonitis
can occur.
High doses , 10 times over recommended (in resistant patients) can
lead to nephrotoxicity.
High-dose regimens must be followed by rescue with folinic acid (a
form of FH4).
Pyrimidine analogues
Fluorouracil, an analogue of
uracil, also interferes with DTMP
synthesis. The result is
inhibition of DNA but not RNA or
protein synthesis.
The main unwanted effects are
gastrointestinal epithelial
damage and myelotoxicity. Two
other drugs, capecitabine and
tegafur, are metabolised to
fluorouracil.
Cytarabine (cytosine arabinoside) is an
analogue of the naturally occurring
nucleoside 2-deoxycytidine. The drug
enters the target cell and undergoes the
same phosphorylation reactions as the
endogenous nucleoside to give cytosine
arabinoside trisphosphate, which inhibits
DNA polymerase.
The main unwanted effects are on the
bone marrow and the gastrointestinal
tract. It also causes nausea and vomiting.
Gemcitabine, an analogue of cytarabine,
has fewer unwanted actions, mainly an
influenza-like syndrome and mild
myelotoxicity. It is often given in
combination with other drugs such as
cisplatin.
Purine analogues
The main anticancer purine
analogues include cladribine,
clofarabrine, fludarabine,
pentostatin, nelarabrine,
mercaptopurine and
tioguanine.
Fludarabine is metabolised to the
trisphosphate and inhibits DNA
synthesis by actions similar to
those of cytarabine.
It is myelosuppressive. Pentostatin
has a different mechanism of
action.
This action interferes with critical
pathways in purine metabolism
and can have significant effects on
cell proliferation.
PLANT DERIVATIVES
Several naturally occurring plant products exert potent
cytotoxic effects and have a use as anticancer drugs.
Vinca alkaloids
The vinca alkaloids are derived from the Madagascar
periwinkle (Catharanthus roseus).
The principal members of the group are vincristine,
vinblastine and vindesine. Vinflumine, a fluorinated
vinca alkaloid, and vinorelbine are semisynthetic vinca
alkaloids with similar properties.
The drugs bind to tubulin and inhibit its polymerisation into
microtubules, preventing spindle formation in dividing cells
and causing arrest at metaphase. Their effects become
manifest only during mitosis. They also inhibit other cellular
activities that require functioning microtubules, such as
leukocyte phagocytosis and chemotaxis, as well as axonal
transport in neurons.
Vincristine has very mild myelosuppressive activity but is
neurotoxic and commonly causes paraesthesias (sensory
changes), abdominal pain and weakness.
Vinblastine is less neurotoxic but causes leukopenia, while
Paclitaxel and related compounds
Taxanes are the active component. Camptothecins.
The group includes paclitaxel and the semi-
The camptothecins irinotecan and
synthetic derivatives docetaxel and topotecan, isolated from the stem of the
cabazitaxel. tree Camptotheca acuminata, bind to and
inhibit topoisomerase I .
These agents act on microtubules, stabilising
them (in effect freezing them) in the Diarrhoea and reversible bone marrow
polymerised state, achieving a similar effect to depression occur but, in general, these
that of the vinca alkaloids.
alkaloids have fewer unwanted effects than
They are generally used to treat breast and lung most other anticancer agents.
cancer and paclitaxel, given with carboplatin, is
the treatment of choice for ovarian cancer.
Unwanted effects, which can be serious, include Etoposide
bone marrow suppression. Resistant fluid Etoposide is derived from mandrake root
retention (particularly oedema of the legs) can (Podophyllum peltatum).
occur with docetaxel. Hypersensitivity to these
compounds is common and requires
it may act by inhibiting mitochondrial
pretreatment with corticosteroids and
antihistamines. function and nucleoside transport, as well
as having an effect on topoisomerase II.
Oestrogens
Diethylstilbestrol and ethinyloestradiol are still occasionally used in the palliative treatment of
androgen-dependent prostatic tumours. These tumours can also be treated with gonadotrophin-
releasing hormone analogues.
Progestogens
Progestogens such as megestrol, norehisterone and medroxyprogesterone have a role in
treatment of endometrial cancer.
Gonadotrophin-releasing hormone analogues
analogues of the gonadotrophin-releasing hormones, such as goserelin, buserelin, leuprorelin
and triptorelin, can, when administered chronically, inhibit gonadotrophin release. These agents
are therefore used to treat advanced breast cancer in premenopausal women and prostate cancer.
The effect of the transient surge of testosterone secretion that can occur in patients treated in this
way for prostate cancer must be prevented by an antiandrogen such as cyproterone. Degaralix is
a gonadotrophin-releasing hormone antagonist used for the treatment of prostate cancer.
Somatostatin analogues.
Analogues of somatostatin such as octreotide and lanreotide, are used to relieve the
symptoms of neuroendocrine tumours, including hormone-secreting tumours of the
gastrointestinal tract such as VIPomas, glucagonomas, carcinoid tumours and gastrinomas.
HORMONE ANTAGONISTS.
In addition to the hormones themselves, hormone antagonists can also be effective in the
treatment of several types of hormone-sensitive tumours.
Antioestrogens
tamoxifen, is remarkably effective in some cases of hormone-dependent breast cancer and may
have a role in preventing these cancers. In breast tissue, tamoxifen competes with endogenous
oestrogens for the oestrogen receptors and therefore inhibits the transcription of oestrogen-
responsive genes. Other oestrogen receptor antagonists include toremifene and fulvestrant.
Unwanted effects are similar to those experienced by women following the menopause.
Potentially more serious are hyperplastic events in the endometrium, which may progress to
malignant changes, and the risk of thromboembolism.
Aromatase inhibitors such as anastrozole, letrozole and exemestane, which suppress the
synthesis of oestrogen from androgens in the adrenal cortex (but not in the ovary), are also
effective in the treatment of breast cancer in postmenopausal (but not in premenopausal)
women,
Antiandrogens
The androgen antagonists
flutamide, cyproterone and
bicalutamide may be used
either alone or in combination
with other agents to treat
tumours of the prostate. They are
also used to control the
testosterone surge (flare) that is
seen when treating patients with
gonadorelin analogues.
MONOCLONAL ANTIBODIES
In some cases, binding of the antibody to its target activates the hosts immune
mechanisms and the cancer cell is killed by complement-mediated lysis or by killer
T cells.
Other monoclonal antibodies attach to and inactivate growth factors or their
receptors on cancer cells, thus inhibiting the survival pathway and promoting
apoptosis.
Unlike most of the cytotoxic drugs described above, they offer the prospect of
highly targeted therapy without many of the side effects of conventional
chemotherapy. This advantage is offset in most instances as they are often given in
combination with more traditional drugs. Several monoclonals are in current clinical
use. Their high cost is a significant problem.
Rituximab: is a monoclonal antibody that is used (in combination with other
chemotherapeutic agents) for treatment of certain types of lymphoma. It is
effective in 4050% of cases when combined with standard chemotherapy.
Unwanted effects include hypotension, chills and fever during the initial infusions
and subsequent hypersensitivity reactions. A cytokine release reaction can occur
and has been fatal. The drug may exacerbate cardiovascular disorders.
Trastuzumab (Herceptin) is a humanised murine monoclonal antibody that binds to
an oncogenic protein termed HER2 (the human epidermal growth factor receptor 2), a
member of the wider family of receptors with integral tyrosine kinase activity. Tumour
cells, in about 25% of breast cancer patients, overexpress this receptor and the
cancer proliferates rapidly. Early results show that trastuzumab given with standard
chemotherapy has resulted in a 79% 1-year survival rate in treatment-naive patients
with this aggressive form of breast cancer. The drug is often given with a taxane such
as docetaxel. Unwanted effects are similar to those with rituximab.
Bevacizumab is a humanised monoclonal antibody that is used for the treatment of
colorectal cancer but would be expected to be useful for treating other cancers too. It
neutralises VEGF (vascular endothelial growth factor), thereby preventing the
angiogenesis that is crucial to tumour survival. A closely related preparation is also
given by direct injection into the eye to retard the progress of acute macular
degeneration (AMD), a common cause of blindness associated with increased retinal
vascularisation.
Catumaxomab attaches to an epithelial adhesion molecule, EpCAM, which is
overexpressed in some malignant cells. The antibody binds to this adhesion molecule
and also to T lymphocytes and antigen-presenting cells, thus facilitating the action of
the immune system in clearing the cancer.
PROTEIN KINASE INHIBITORS
Imatinib; is a small-molecule inhibitor of signalling pathway
kinases. It inhibits an oncogenic cytoplasmic kinase (Bcr/Abl),
considered to be a unique factor in the pathogenesis of chronic
myeloid leukaemia (CML). Unwanted effects include
gastrointestinal symptoms (pain, diarrhoea, nausea), fatigue,
headaches and sometimes rashes. Resistance to imatinib,
resulting from mutation of the kinase gene, is a growing
problem. It results in little or no cross-resistance to other
kinase inhibitors.
TARGETS FOR DRUG ACTION
The molecular target in general
can be broadly divided into:
receptors
ion channels
enzymes
transporters (carrier molecules).
Ion channels, are essentially
gateways in cell membranes that
selectively allow the passage of
particular ions, and that are
induced to open or close by a
variety of mechanisms.
Transporters: In many cases, hydrolysis of ATP provides the energy for transport of substances against their electrochemical
gradient. Such transport proteins include a distinct ATP binding site, and are termed ABC (ATP-binding cassette)
transporters. multi-drug resistance (MDR) transporters that eject cytotoxic drugs from cancer and microbial cells, conferring
resistance to these therapeutic agents .
Receptor Proteins- Cloning of
receptors
In the 1970s, pharmacology entered a new phase when receptors,
which had until then been theoretical entities, began to emerge as
biochemical realities following the development of receptor-
labelling techniques.
Receptors are proteins normally embedded in membrane lipid and
thus have proven very difficult to crystallise.
Obtaining crystals of a protein allows its structure to be analysed at
very high resolution by X-ray diffraction techniques.
Now that the genes have been clearly identified, the emphasis has
shifted to characterising the receptors pharmacologically and
determining their molecular characteristics and physiological
functions.
TYPES OF RECEPTOR
Receptors elicit many different types of cellular effect.
Some of them are very rapid, such as those involved in
synaptic transmission, operating within milliseconds,
whereas other receptor-mediated effects, such as those
produced by thyroid hormone or various steroid
hormones, occur over hours or days.
Despite the individual differences between the members of a family of receptors the general
structure and the attached transduction signal machinery is moistly similar
There are subtypes of receptors in a same family and
regularly new members and isoforms are described.
www.guidetopharmacology.org
For the general description of ligand-gated ion channel structure we use has a model the
nicotinic acetylcholine receptor, which we find at the skeletal neuromuscular junction.
Gs and Gi produce, respectively, stimulation and inhibition of the enzyme adenylyl cyclase
The subunits of these G proteins differ in structure. One functional difference that has been
useful as an experimental tool to distinguish which type of G protein is involved in different
situations concerns the action of two bacterial toxins, cholera toxin and pertussis toxin.
These toxins, which are enzymes, catalyse a conjugation reaction (ADP ribosylation) on the
subunit of G proteins. Cholera toxin acts only on Gs, and it causes persistent activation. Many of
the symptoms of cholera, such as the excessive secretion of fluid from the gastrointestinal
epithelium, are due to the uncontrolled activation of adenylyl cyclase that occurs. Pertussis toxin
specifically blocks Gi and Go by preventing dissociation of the G protein trimer.
TARGETS FOR G PROTEINS
adenylyl cyclase, the enzyme responsible for cAMP formation
Rho A/Rho kinase, a system that regulates the activity of many signalling pathways
controlling cell growth and proliferation, smooth muscle contraction, etc.
mitogen-activated protein kinase (MAP kinase), a system that controls many cell
functions, including cell division.
cAMP is a nucleotide synthesised within the cell from ATP by the action of a
membrane-bound enzyme, adenylyl cyclase. It is produced continuously and
inactivated by hydrolysis to 5-AMP by the action of a family of enzymes
known as phosphodiesterases
Many different drugs, hormones and neurotransmitters act on GPCRs and
increase or decrease the catalytic activity of adenylyl cyclase, thus raising
or lowering the concentration of cAMP within the cell. In mammalian cells
there are 10 different molecular isoforms of the enzyme, some of which
respond selectively to Gs or Gi
A common pthway of the AMPc is brought about by the activation of protein
kinases by cAMP primarily protein kinase A (PKA) in eukaryotic cells.
Protein kinases regulate the function of many different cellular proteins by
controlling protein phosphorylation.
increased cAMP production in
response to -adrenoceptor
activation affects enzymes
involved in glycogen and fat
metabolism in liver, fat and
muscle cells. The result is a
coordinated response in
which stored energy in the
form of glycogen and fat is
made available as glucose to
fuel muscle contraction.
As mentioned above,
receptors linked to Gi rather
than Gs inhibit adenylyl
cyclase, and thus reduce
cAMP formation. Examples
include certain types of
mAChR (e.g. the M2 receptor
of cardiac muscle), 2
adrenoceptors in smooth
muscle and opioid receptors.
Adenylyl cyclase can be
Most are weakly inhibited by drugs such as
methylxanthines (e.g. theophylline and caffeine; see
Chs 28 and 48). Rolipram (used to treat asthma; Ch.
28) is selective for PDE4, expressed in inflammatory
cells; milrinone (used to treat heart failure; Ch. 21) is
selective for PDE3, which is expressed in heart muscle;
sildenafil (better known as Viagra; Ch. 35) is selective
for PDE5, and consequently enhances the vasodilator
effects of nitrous oxide (NO) and drugs that release NO,
whose effects are mediated by cGMP (see Ch. 20).
The phospholipase C/inositol phosphate system
One particular member of the PI family,
namely phosphatidylinositol (4,5)
bisphosphate (PIP2), which has
additional phosphate groups attached
to the inositol ring, plays a key role.
PIP2 is the substrate for a membrane-
bound enzyme, phospholipase C
(PLC), which splits it into diacylglycerol
(DAG) and inositol (1,4,5) trisphosphate
(IP3;), both of which function as second
messengers as discussed below (p. 35)
Inositol phosphates and intracellular calcium
Folate antagonists.
The main folate antagonist is
methotrexate, one of the
most widely used
antimetabolites in cancer
chemotherapy.
Prodrugs
biologically erodible nanoparticles
antibodydrug conjugates
packaging in liposomes
coated implantable devices.
Also, fluorescence methods have been developed to
study the kinetics of ligand binding and subsequent
conformational changes associated with activation (see
Lohse et al., 2008; Bockenhauer et al., 2011).
Routes of administration
First Category: There are four groups (AD) of routes of administration in this category; they all
share a common feature of having a biological barrier. The structure of some barriers can be as
complex as the gastrointestinal wall and some as basic as sublingual or rectal mucosa.
Xenobiotics must pass through these barriers to reach the systemic circulation and exhibit the
expected or unexpected systemic effect.
Second Category: The routes of administration in this category circumvent the barriers, and are
used for immediate onset of action and direct access to the systemic circulation.
Third Category: Interaction of xenobiotics with the skin can lead to local and/or systemic effect.
In addition to the physicochemical characteristics of xenobiotics and their vehicle, environmental
Fourth Category:
Specialized routes of
administration for
achieving local and
targeted therapy are
included in this category.
Although the intended use
of these routes is mostly to
achieve local or targeted
effect, nonetheless a
portion of administered
dose may reach the
systemic circulation and
exhibit systemic effect.